In a variety of neurodegenerative disorders such as ischemia and Alzheimer's disease (Hayashi et al., Neuropathol. Appl. Neurobiol. (2000) 26:390-97; Rashidian et al., Biochim. Biophys. Acta. (2007) 1772:484-93; Vincent et al., J. Cell. Biol. (1996) 132:413-25.; Yang et al., J. Neurosci. (2001) 21:2661-68), neurons engage in aberrant cell cycle activities, expressing cell cycle markers such as Ki-67 and PCNA, and undergoing a limited extent of DNA replication (Yang et al., J. Neurosci. (2001) 21:2661-68). This behavior is remarkable considering that neurons have terminally differentiated during development and remain quiescent for decades prior to the onset of these events. While the underlying mechanisms are poorly understood, multiple lines of evidence suggest that these activities play an early and contributory role in neuronal death (Andorfer et al., J. Neurosci. (2005) 25:5446-54; Busser et al., J. Neurosci. (1998) 18:2801-07; Herrup et al., Development. (1995) 121:2385-95; Nguyen et al., Cell Death Differ. (2002) 9:1294-306.). For example, overexpression of cell cycle activity-inducing proteins such as SV40 large T antigen, c-myc, c-Myb, or E2F-1 causes neuronal death in vitro and in vivo (al-Ubaidi et al., Proc. Natl. Acad. Sci. USA (1992) 89:1194-98.; Konishi et al., J. Neurosci. (2003) 23:1649-58; Liu et al., Neuron. (2001) 32:425-38; McShea et al., Biochim. Biophys. Acta. (2007) 1772:467-72), while pharmacological inhibitors of CDKs or other cell cycle components can exert neuroprotective effects (Padmanabhan et al., J. Neurosci. (1999) 19:8747-56).
DNA damage may also be involved in multiple conditions involving neuronal death (Adamec et al., Brain Res. (1999) 849:67-77; Ferrante et al., J. Neurochem. (1997) 69:2064-74; Hayashi et al., Brain Res. (1999) 832:159-63; Kruman et al., Neuron. (2004) 41:549-61; Robison et al., J. Neurol. Sci. (1984) 64:11-20). For example, oxidative damage to neuronal DNA has been observed in rodent models of ischemia (Hayashi et al., Brain Res. (1999) 832:159-63). Accumulation of reactive oxygen species results in DNA damage, cell cycle activity, and neurodegeneration in mutant mice with disrupted apoptosis-inducing factor (AIF) (Klein et al., Nature (2002) 419:367-74). In addition, congenital syndromes with DNA repair gene mutations, such as ataxia telangiectasia and Werner's syndrome, display a progressive neurodegeneration phenotype, demonstrating the importance of maintaining DNA integrity in the adult brain (Rolig et al., Trends Neurosci. (2000) 23:417-24). Importantly, DNA damage is involved in the aging of the human brain (Lu et al., Nature (2004) 429:883-91), which suggests that DNA damage may play a role in age-dependent neurological disorders as well.
Nucleosomes, the primary scaffold of chromatin folding, are dynamic macromolecular structures, influencing the conformation of chromatin in solution. The nucleosome core is made up of the histone proteins, H2A, H2B, H3 and H4. Histone acetylation causes nucleosomes and nucleosomal arrangements to behave with altered biophysical properties. The balance between the activities of histone acetyl transferases (HAT) and histone deacetylases (HDAC) determines the level of histone acetylation. Acetylated histones cause relaxation of chromatin and activation of gene transcription, whereas deacetylated chromatin generally is transcriptionally inactive.
HDACs have been grouped in four classes depending on sequence identity, domain organization, and function: Class I: HDAC1 (histone deacetylase 1), HDAC2, HDAC3, HDAC8; Class II: HDAC4, HDAC5, HDAC6, HDAC7, HDAC9, HDAC10; Class III: SIRT1, SIRT2, SIRT3, SIRT4, SIRT5, SIRT6, SIRT7; and Class IV: HDAC11. Within Class I, HDAC1, HDAC2 and HDAC8 are primarily found in the nucleus while HDAC3 and Class II HDACs can shuttle between the nucleus and the cytoplasm. Class III HDACs (the sirtuins), couple the removal of the acetyl group of the histone to NAD hydrolysis, thereby coupling the deacetylation reaction to the energy status of the cell.
A need remains for new compounds and treatment options that result in the protection of cells, including neuronal cells to DNA damage. The suppression of DNA damage in neuronal cells is an important mechanism for suppressing neuronal cell death and provides an opportunity for the treatment or prevention of various neurological disorders.